In several human syndromes which are predisposed to cancer, the patients' normal cells usually exhibit a high frequency of spontaneous chromosome damage (e.g. Fanconi anemia) or an abnormally high rate of chromosome damage induced by UV (e.g. xeroderma pigmentosum). In some familial cancer (e.g. MEA-II), patients' normal cells also show a relatively high frequency of spontaneous chromosome aberrations, indicating genetic instability. It is probable that genetic instability in the human population forms a gradient, from very stable to highly unstable and that persons with more unstable genomes may be more susceptible to the effects of tumorigenic agents, both externally and internally. Thus it is possible that genetic instability (as monitored by chromosome instability) may occur more frequently in cancer patients than normal, healthy subjects chosen at random. However, if this hypothesis proves to be valid, a proportion of "normal" persons should also exhibit some degree of genetic instability since some of them will eventually become cancer patients. Among normal persons, the spontaneous chromosome aberration frequency may be too low to procure statistical significant data (even cells of xeroderma pigmentosum patients show a normal rate of spontaneous aberrations). To differentiate "normal" persons with very stable genomes from those with slightly unstable genomes, we plan to challenge the cultured lymphocytes with clastogens to artificially induce DNA lesions in order to estimate the degree of damage, including deficiencies in repair mechanisms. We plan to use bleomycin, TEM, and actinomycin D to induce chromosome breakage and mitomycin C to induce sister chromatid exchanges. This proposed project is designed to find out the feasibility of the cytogenetic approach to genetic epidemiology (using peripheral blood samples of both cancer patients and normal persons) by exploring a variety of experimental protocols. It is not an actual survey of the human population which may come after this concept is verified and the protocols standardized. Preliminary results indicate that this approach may yield significant information. The results may explain why under similar environments (or personal habits) some persons develop cancer more easily than others; and protocols to be developed may be used eventually to monitor human subjects.